Do corticosteroids affect immunotherapy efficacy in malignancy? – A systematic review

Abstract Background Early studies indicated that corticosteroids may limit the survival benefit from immunotherapy. We conducted this systematic review to evaluate the effect corticosteroids have on immunotherapy in patients with malignancy, when adjusted for potentially confounding effects of corticosteroids given for palliative indications. Methods Three electronic databases (PubMed, Embase and Medline) were searched on 1 February 2023. Studies that measured response or survival to immunotherapy in people receiving corticosteroids for non‐cancer indications compared to either no corticosteroids or corticosteroids for cancer‐related indications were included. Studies exclusively evaluating the effect of corticosteroids administered for immune‐related adverse events (irAE) were excluded to avoid immortal time bias. Pooled odds and hazard ratios with 95% confidence intervals (CI) were calculated using a random effects model. Study heterogeneity was assessed using the I 2 statistic, and publication bias was evaluated by funnel plot and Egger's regression model. Results Eight thousand four hundred and twenty‐six titles were identified on our search. Eight studies met our inclusion criteria for meta‐analysis. Administration of corticosteroids does not have a statistically significant effect on survival and response to immunotherapy when administered for non‐cancer‐related indications, with a pooled odds ratio for overall response rate 1.01 (95% CI 0.64–1.60); pooled hazard ratio (HR) for progression free survival 0.87 (95% CI 0.68–1.12); and pooled HR for overall survival 0.79 (95% CI 0.59–1.05). Conclusion This systematic review indicates that administration of corticosteroids does not affect response to immunotherapy nor survival outcomes, when removing confounding palliative corticosteroid indications. These results are limited by the retrospective nature of the studies included, small sample sizes, lack of information about corticosteroid dosing and the inclusion of irAE in two of the studies which could bias the results.


| INTRODUCTION
Immune checkpoint inhibitors (ICI) have revolutionised medical care for patients with malignant diseases, with prolonged responses observed more frequently than with chemotherapy alone.Despite impressive results seen with ICI, most patients do not achieve a sustained clinical response and markers that could predict response, or overcome resistance mechanisms are highly valuable.Corticosteroids are predominantly used for immunosuppression or modulating toxic effect from ICI, thus raising a concern that corticosteroids might also diminish the anti-cancer effect.
0][11][12][13] These reports led clinicians to aggressively down titrate corticosteroid doses prior to ICI, or delay initiation of ICI.Iglesias-Santamaría et al. however, reported in 2020 no effect on immunotherapy by concurrent corticosteroids, but noted a negative impact with concurrent use of opioids. 14se of corticosteroids in patients with cancer is often associated with poor performance status, [15][16][17][18] and a report by Facchinetti et al. suggested that people with poor performance status have poorer prognosis with immunotherapy, 19 which could suggest that the observed interaction of corticosteroids with ICI might be confounded.
Several inconsistencies regarding the potential interaction between ICI and corticosteroids need discussion.][22] Secondly, there are conflicting results about the association between the effects of corticosteroids on survival when used for the treatment of irAE.][35] Lastly, Ricciuti et al. reported that negative impact on survival was observed in patients prescribed corticosteroids particularly for palliative or cancer related indications. 36[38][39][40][41][42] In this systematic review we propose that the negative impact of corticosteroids on ICI therapy is not causative, but rather a confounding effect due to the correlation of corticosteroid therapy with poor performance status or an aggressive disease phenotype.We conducted a systematic literature review for articles that reported comparison of parameters of efficacy such as OS, PFS or response rate in patients treated with ICI in combination with corticosteroids, and detailed the indication for which the corticosteroids were prescribed.Studies looking at such survival parameters with regard to systemic corticosteroid therapy exclusively for irAE were excluded due to the possible effect of immortal time bias (ITB) on survival. 43,446][47] Wang et al. published a similar analysis in 2021 8 but did not include smaller studies that only reported response rates, and since their report another study was published 42 and is therefore worth updating for a stronger result.

| Eligibility criteria
Any phase II/III randomised control trials, case control studies and cohort studies were considered for inclusion.
Only full text articles were eligible, abstracts and conference reports were excluded.Studies had to describe any solid or haematological malignancy in human patients with any type of ICI, with information regarding indications for steroid administration stratified by cancer-related and non-cancer-related.The main clinical outcomes in the studies had to be reported as OS, PFS or objective response rate (ORR).Studies that did not report any of these outcomes but had available information regarding the response of each participant in the cohort were also included and response rate was calculated.Studies were ineligible for inclusion if they were case series or case reports, used immunotherapy for non-cancer indications or did not report the indications for corticosteroid use.Animal nonhuman studies were also excluded.Studies that exclusively evaluated the effects of corticosteroids on survival when prescribed for management of irAE were excluded as it was previously reported to not affect the survival outcome of patients, and including data from such studies would likely cause an ITB in favour of the hypothesis.

| Search strategy
Our systematic review was performed following the preferred reporting items for systematic reviews and metaanalyses (PRISMA) statement. 48

| Study selection
Eligible studies were included if the following were described: (1) An interventional or observational study design of human patients with any malignancy treated with immune-checkpoint inhibitors; (2) Reported risk ratios and 95% confidence intervals (CI) of OS, PFS or ORR comparing patients requiring corticosteroids for cancer-unrelated reasons versus corticosteroids for cancer related reasons, or versus no corticosteroids.Studies that did not report risk ratios and 95% CI but reported data such that risk ratios and 95% CI could be manually calculated, were also included.
Studies that exclusively reported risk ratios of patient outcomes with corticosteroids for immune-related adverse events were excluded, due to the potential for ITB. 43,44

| Data extraction
Two reviewers (YB and SYL) extracted data from included studies.First author name, year of publication, study design, sample size, malignancy type, stage of malignancy, immune-checkpoint inhibitor type, steroid indication and comparison group and reported outcomes were extracted.

| Statistical analysis
Pooled hazard ratios and 95% CI for OS and PFS were calculated using a random-effects model.A pooled odds ratio and 95% CI were calculated using a random-effects model for objective response rate. 49Publication bias was examined using Egger's regression test. 50Study heterogeneity was measured using the I 2 statistic. 51A p < 0.05 was defined as statistically significant.Statistical analyses were performed using Comprehensive Meta-analysis version 3.3.070,Englewood, NJ, USA (2014).

| RESULTS
7][38][39][40][41][42] Table 1 shows the characteristics of the included studies.41,42 The majority of studies analysed patients with stage IV malignancies.Four studies compared patients without systemic corticosteroids versus those with systemic corticosteroids, while four studies analysed patients with <10 mg equivalent of prednisolone versus patients with ≥10 mg equivalent of prednisolone. 36,37,41,42nly two of the selected studies assessed response differences due to baseline or concurrent corticosteroid use, 38,41 due to the small number of patients in those studies, this factor was not assessed on this analysis.
Figure 2 shows the meta-analysis of five studies with a total sample size of 1453 patients for the risk of corticosteroids for non-cancer-related indications on objective response rates of immunotherapy.Corticosteroids were not statistically associated with objective response rate, with a pooled odds ratio of 1.01 (95% CI 0.64-1.60).There was no significant heterogeneity, with I 2 = 0.0%.There was no evidence of publication bias, with Egger's test p = 0.91.
Figure 3 shows the meta-analysis of five studies with a total sample size of 2409 patients for the risk of corticosteroids for non-cancer-related indications on PFS with immunotherapy.There was no statistically significant association with corticosteroid use, with a pooled hazard ratio of 0.87 (95% CI 0.86-1.12).There was no significant heterogeneity, with I 2 = 7.4%.There was no evidence of publication bias, with Egger's test p = 0.62.
Figure 4 shows the meta-analysis of five studies with a total sample size of 2409 patients for risk of corticosteroids for non-cancer-related indications on OS with immunotherapy.Corticosteroids were not statistically associated with OS, with a pooled hazard ratio of 0.79 (95% CI 0.59-1.05).There was no significant heterogeneity, with I 2 = 0.0%.There was no evidence of publication bias, with Egger's test p = 0.68.

| DISCUSSION
Our systematic review found that there is no difference in response rates or survival outcome for administration of corticosteroids to patients being treated for their malignancy with ICI.It is not possible to conclude from this analysis that corticosteroids do not have any detrimental effect on ICI due to the lack of information regarding doses and length of treatment with corticosteroids.Moreover, high doses of corticosteroids given for prolonged periods are associated with multiple potential complications and should not be considered safe based on this analysis.
6][27][28][29][30][31][32] The association with irAE however, is reported to potentially be affected by ITB, 43,44 and is likely to also be confounded by the immunogenic nature of some tumours.ITB can occur in analyses of survival in patients being treated with ICI, as a longer duration of ICI treatment is associated with higher risk of developing irAEs, 52,53 and therefore by definition will be associated with longer survival, whereas patients with shorter survival and therefore shorter duration of treatment will likely have a lower risk of developing irAE.Multiple studies including Weber et al. and Shimozaki et al. reported a statistically significant longer time on therapy with ICI in patients who experienced an irAE when compared to those who did not experience an irAE. 52,53ang et al. reported on a pooled analysis of 23 clinical trials and 8436 patients.The reported pooled median time for development of grade 3-4 irAE was 4.6-12.2weeks for CTLA-4 inhibitors, and 14.1-123.4weeks for PD-1/PD-L1 inhibitors. 54n contrast to assessment on the effect of corticosteroids on response to ICI when used for irAE, assessment on the use of corticosteroid for non-cancer-related indications should not be affected by ITB, as the use and duration of corticosteroids for non-cancer-related indications should not be affected by the use and duration of immunotherapy for cancer.In the papers selected for this analysis, administration of corticosteroids was predominantly for unrelated autoimmune diseases which was reported to be at baseline or prior to initiation of ICI therapy, or for treatment of exacerbation of chronic airway disease which logically should not have any biological relation to ICI therapy.This analysis does have several limitations however.Firstly, all the studies in our analysis were retrospective, and therefore would have a high risk of being affected by various selection biases.The studies reported on relatively small number of patients treated with corticosteroids for non-cancer indications, and did not comprehensively report the doses and length of treatment with corticosteroids.Timing of corticosteroid therapy (baseline vs. concurrent) was only mentioned in two studies.These limitations weakens the ability to conclude that any dose of corticosteroids for any length of time is unlikely to harm the response to ICI, as it is possible that the studies only looked at low doses for a short course, and thus might undervalue a possible negative effect of corticosteroids on response to ICI.
Lastly, two studies in our meta-analysis 38,41 included patients who received corticosteroids for irAE and could have been affected by ITB, one study did not explicitly detail which indications were considered by the authors as non-cancer indications 42 and one study detailed the non-cancer indications as 'other inflammation process non-related to cancer'. 37The ambiguity of these definitions could potentially weaken the recommendation as these trials may have potentially included patients with corticosteroid treatment of irAE, thus further enhancing ITB.
Interestingly, Bai et al. reported a retrospective analysis of 509 patients with melanoma who developed irAE.In that study a comparison of survival outcomes was made between patients who required high doses of corticosteroids, defined as more than 60 mg per day of oral prednisolone equivalent, and patients who developed irAEs not requiring high doses of corticosteroids.To minimise ITB the analysis used landmarks of 8 and 26 weeks from initiation of ICI, and patients who had disease progression or died prior to the landmark were excluded from the analysis.This study did report inferior survival parameters for irAE requiring high doses of corticosteroids and is certainly worth consideration. 55here is however a potential confounding effect of these results by the possibilities that patients who require higher doses of corticosteroids are likely to have a longer delay to treatment re-challenge, might be excluded from further ICI altogether or might have developed other complications from immunosuppression that could have a negative effect on survival.
While it is not possible to conclude from the results of this meta-analysis that high doses for prolonged periods of time will not affect the prognosis of cancer patients treated with ICI, and a specific safety threshold for corticosteroid dosing cannot be established from this analysis, our results do suggest that doses and durations of corticosteroids used commonly for non-cancer-related indications do not have a significant effect on response or survival in patients treated with ICI for malignancy.Avoidance of sensible prescribing of corticosteroids for COPD exacerbations, autoimmune disease flares or irAE in the hope of preserving ICI efficacy is therefore not likely to be beneficial.

| CONCLUSION
The results of this meta-analysis suggest that there is no difference in outcome when corticosteroids are administered concurrently with ICI.This previously reported association of poor response to ICI when co-administered with corticosteroids is likely to be due to the confounder effect of the indication for which corticosteroids are being prescribed.Corticosteroids are often prescribed to patients with a more aggressive disease, which is in itself a poor prognostic marker with regard to response and survival, 19 and is therefore the likely explanation for the observed association.The results of this meta-analysis suggests that there should not be any expected benefit from rapid reduction of doses or avoidance of administration of corticosteroids to patients treated with ICI when indicated, as it is not likely to affect the outcome when prescribed for non-cancer indications.Corticosteroid administration is similarly unlikely to affect response when prescribed for cancer-related indications as the main limitation to the effect of ICI is likely to be the disease phenotype, rather than administration of corticosteroids.This analysis has Two reviewers (YB and SYL) searched MEDLINE, EMBASE and PubMed databases from inception to 1 February 2023.The search terms [(pembrolizumab OR ipilimumab OR nivolumab OR durvalumab OR avelumab OR atezolizumab OR cemiplimab OR tremelimumab OR dostarlimab OR spartalizumab OR camrelizumab OR sintilimab OR tislelizumab OR toripalimab OR ctla4 OR PD1 OR PD-1 OR PD-L1 OR 'immune checkpoint inhibitors') AND (glucocorticoids OR steroids OR glucocorticosteroids OR prednisolone OR prednisone OR dexamethasone OR methylprednisolone OR hydrocortisone OR cortisone OR beclomethasone OR betamethasone OR triamcinolone) AND (malignancy OR cancer OR neoplasms)] were used.No language limitations were placed.All included studies were searched via Google Scholar for citing references, and the reference lists of included studies were hand searched.Disagreements were resolved by a third reviewer (MT).

centre Total no of pts Cancer Stage Immunotherapy Steroid indication and doses of groups analysed Group 1: no/minimal steroids Group 2: steroids given with ICI Outcome reported (Group 1 vs.Group 2)
E 1 Flow diagram for studies selected.

Study Study type Single/multi centre Total no of pts Cancer Stage Immunotherapy Steroid indication and doses of groups analysed Group 1: no/minimal steroids Group 2: steroids given with ICI Outcome reported (Group 1 vs.Group 2)
Forest plot for objective response.
F I G U R E 2 F I G U R E 3Forest plot for progression free survival.